PNPLA3 Variants Specifically Confer Increased Risk for Histologic Nonalcoholic Fatty Liver Disease But Not Metabolic Disease

Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. It is frequently associated with obesity, insulin resistance and features of the metabolic syndrome.1,2 The histologic phenotype of NAFLD extends from fatty liver to steatohepatitis.3 Nonalcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, inflammation, and cytologic ballooning with varying degrees of fibrosis.3 NASH progresses to cirrhosis in approximately 15% of subjects.4 The factors that predispose to the risk of progression and the mechanisms that drive disease progression in those who develop cirrhosis are not well understood. Recently, genetic association studies successfully identified genetic variants that associate with many polygenic diseases and traits.5 Seven genetic variants were associated with liver function tests (LFTs) (near PNPLA3, CPN1, ABO, GPLD1, JMJD1C, GGT1, HNF1A).6,7 An allele in PNPLA3-(rs738409[G] encoding L148M) was also associated with an increased risk of hepatic steatosis by magnetic resonance spectroscopy.6,8,9 PNPLA3, also known as patatin like phospholipase-3 or adiponutrin, is expressed in adipose tissue10 and has recently been shown to function as a lipase.11 Elevations of liver enzymes are nonspecific markers of hepatocyte injury and liver imaging is an indirect measure of liver fat that can be influenced by other components in liver, including glycogen, iron and water content. The objective of the current study was to determine the impact of genetic variants that associate with LFTs or liver steatosis by magnetic resonance spectroscopy on histologically-defined NAFLD in subjects with histologically-characterized NAFLD from the NASH Clinical Research Network (CRN).